Although oral sustained release drug delivery systems have attracted considerable attention for the last forty years, technologies for prolongation of gastric residence time of drugs are reasonably recent. Gastric emptying can vary from less than an hour to more than six hours between different subjects and within the same subject. In addition, there is considerable variation in drug absorption from site to site within the gastrointestinal tract. These two aspects can adversely affect the level of bioavailability and the degree of prolongation of an effective plasma level achievable by a conventional sustained release dosage form. Prolongation of residence in the stomach of a dosage form system with sustained drug release properties can have a significant enhancing effect on bioavailability and hence drug effectiveness. Drug being slowly and continuously released at a predetermined rate in the stomach can reach the absorption site in the small intestine in an absorbable state, i.e as a solution or fine dispersion.
During the last 15 years, technologies such as swelling polymers, bioadhesive polymers and inflatable devices in either single or multi-unit systems have been actively investigated. Although drug retention and drug release tested in vitro from most oral prolonged residence delivery systems can be foreseen and maintained between reasonable limits, the lack of in vivo correlation has been evident.
Physiological factors such as pH and motility of the stomach and the fasted and fed state of the subjects have been found to have a profound effect on the gastric residence time of drug delivery systems. Since the stomach is rarely considered a site of drug absorption, most, if not all, sustained release dosage forms have been designed to release the drug through the gastrointestinal tract.
A recent study suggested that the microorganism Helicobacter pylori is a major factor in the development of gastric ulcer. It has also been found that about 60% and 40% of the Helicobacter pylori are embedded in the fundus and the body regions of the stomach, respectively. For an efficient treatment, a sustained site-specific release of antibiotic to the gastric mucosa is advantageous.
The natural function of the stomach is to temporarily store, mechanically break down and disrupt by acid (hydrochloric acid secreted by parietal cells) and enzyme (pepsinogen secreted by chief cells and converted by the gastric acid into pepsin) the chemical bonds associate with ingested food. The stomach is a hollow elastic organ which varies in shape and size between individuals and in a single individual, depending on size and type of ingested meal.
Anatomically, the stomach may be divided into four main regions:    i) Cardia: the smallest part of the stomach and within 3 cm of the junction with the esophagus. The cardia is rich in mucus glands whose secretion is necessary to protect the esophagus from the acid and enzymes of the stomach.    ii) Fundus: the upper part of the stomach superior to the junction between the stomach body and the esophagus.    iii) Body: the largest part of the stomach, responsible for mixing of ingested food and secretion gastrin.    iv) Pylorus: the lower curved part of the stomach which connects the body with the pyloric canal which empties the stomach content into the duodenum. The pyloric glands are mostly involved in the secretion of mucus.
The stomach activity can be divided into three phases:    v) The cephalic phase in which the secretion of gastric fluids such as acids, enzymes and salts, and the motility of the digestive system is stimulated by seeing, smelling, tasting of or even thinking about food.    vi) The gastric phase, which is a continuity of the previous phase and is promoted with the arrival of food to the stomach. The gastric phase is associated with stomach stress and increase in the secretion of hydrochloric acid and enzymes. In fasting subjects, the stomach pH may be as low as 1.5. Food ingestion (particularly milk) will initially neutralize the stomach content to as high as pH 6.0, (7) during which the saliva amylase continues acting on the carbohydrate. The presence of food in the stomach triggers further secretion of hydrochloric acid, which can continue for up to two hours. Low pH of the stomach content will inhibit the amylase activity to create a new environment for pepsin activity.    vii) The intestinal phase which is usually initiates a few hours after the arrival of food and when the first chyme is delivered to the duodenum. The arrival of the chyme to the intestine triggers new sets of hormones, enzymes and buffers that coordinate the activities.
There are several basic principles by which drug from an oral solid dosage form can be delivered to the stomach for either local or systemic absorption. Each principle has its own advantages and limitations. Amongst these technologies are:
1. Swelling and Expanding Systems.
Dosage forms that swell and change their density in relation to their surrounding, gastric content, can be retained in the stomach content for longer than other conventional dosage forms. In the first instance, the device may sink down in the gastric content and then, by physically changing, may acquire low density and thereby float to the surface. A monolithic device comprising of drug and swelling agent may absorb water and swell to form a soft gelatinous outside surface and float on the surface whilst maintaining its integrity for a pre-determined time. Hydration and swelling alone would not be enough to significantly change the device density. Hence addition of a small amount of fatty material may be necessary to impede wetting and improve floating (4). The level and type of the swelling agent and the fatty substances have a significant effect on the final swelling and floating characteristics of the device. Swelling also significantly increases the dosage form size, which has been found to influence the transit properties. The stomach discharges its contents including the non-disintegrated solid dosage form, through the pylorus into the intestine.
A non-disintegrating solid dosage form of a manageable size for swallowing may freely pass the pylorus. A solid dosage form that can swell fairly quickly in the gastric contents can be retained in the stomach until the size is reduced, for example, by erosion. Such enlarged dosage forms should not block the pylorus and the size reduction should be gradual to prolong its residency. The premature gastric emptying of the dosage form could lead to swelling and obstruction of the duodenum.
There are several contradictory reports on the effect of dosage form size on residency. A definite cut-off size of a dosage form for appropriate gastric retention is very difficult to specify due to fasted, fed and individual variations (5,6).
The most common approach to this type of technology is to encapsulate a core containing drug and swelling agent. Such agents can expand 2-50 fold (7) when gastric fluid permeates through the coat. When all the soluble content is released the device collapses and discharges through the pylorus.
Another approach is a solid dosage form containing drug, swelling agent and one or more erodible polymers such as high viscosity Hydroxy propylmethy cellulose and the acid soluble Eudragit E. In the gastric media the device swollen to a larger size that can not pass through the pylorus until the size is reduced by erosion. The gastric residence time can be prolonged as long as food and water are maintained in the stomach.
The technology has attracted many academic and commercial organisations but so far has failed to be developed into more than one product (8). Intra- and inter-variation between individuals and the difficulty of maintaining the fed state are obstacles which need to be overcome to allow further progression of this technology.
A folded sheet dosage form to increase time residency was a subject of an early patent (24) for veterinary use. Initially the drug is loaded into a water-insoluble diffusable polymer and cast into a thin sheet. The sheet is then manually rolled and fed to the animal either directly or after encapsulation (24). In the stomach the folded sheet reopens to its original size and shape. The opened sheet should be large enough so as not to pass the pyloric sphincter.
Several human studies on the transit of non-disintegrated solid dosage form have shown that the pyloric sphincter can only pass solid object smaller than 8 mm. A similar study has carried out using a non-disintegrating polyethylene geometrical shape (20 mm tetrahedron) spiked with a radioactive marker. The device showed a median retention time of 6.5 hour in fed subjects but a less significant 3 hours median time in fasted subjects (25).
In an animal study, non-disintegrating capsule shaped tablets (22.0×8.5×5.1 mm) were retained in the pig stomach for up to 6.0 hours. In contrast, fine powder and solution was transported out of the stomach in a very fast manner (26).
Therefore, a fully opened rectangular sheet, 10 mm2 or larger in area, should not practically pass the pyloric sphincter unless fragmented or collapsed. The acidic environment and the presence of gastric enzymes could also play a major role in the disruption and elimination of the sheet after a predetermined time of residency. The limitations of this technology are the reproducible cutting, folding, maintaining the shape and filling the folded sheet into capsule shells.
2. Floating and Buoyancing System.
The basic principle of this system is to trap gases within sealed encapsulated cores that can float over the gastric content and so be retained in the stomach for a longer time (9-12). Due to the buoyancy effect, this system can provide a protective layer preventing the reflux of gastric content into the esophageal region and can also be used for controlled release devices.
The development of this system is based on two main techniques. The first system is made of hollow cores containing drug and coated with protective membrane. The trapped air in the cores will help the system to float on the gastric content until all or most of the soluble ingredients are released and the system collapses.
The second system is made of cores that, in addition to the drug, contain chemical substances, which generate gases when activated. Coated cores, for example, containing carbonate and/or bicarbonate generate carbon dioxide in the reaction with the hydrochloric acid in the stomach or incorporated organic acid in the system. The generated and trapped carbon dioxide within the encapsulated core help in floating the device. The inflated device later collapses and clears from the stomach when the generated gas permeates slowly through the protective coat.
The major setbacks of these technologies are the different level of hydration and swelling of the agents under different stomach condition. The gastric pH and presence of water and foods have an unpredictable effect on the swelling agents. The time required for swelling and deflation and/or erosion dictate the successfulness of the system and the gastric residence time. Delay in the swelling or fast deflation or erosion will cause early transit of the device to the duodenum.
It is well observed and documented that presence of food and water in the stomach has a significant effect on the residency of non-floating and floating devices (12-14). A human study of the retention time of floating capsules and tablet devices showed that the devices may be retained for up to 4 hours in fed subjects compared to only 2 hours in fasted subjects (15). Other factors affecting the hydration speed and degree will inevitably change the residence time of the floating dosage form. Film forming polymer should be carefully selected to fulfil specific needs. Film hydration and permeability are two more important factors to be carefully considered. These publications recommend that the film should easily permit water and chloride ion (if it is needed for gas evolution), have good elasticity, and release the drug whilst retaining the evolved gas for a considerable time.
In general the effectiveness of the floating system is determined by the subjects conditions (fast and fed), presence of water and the body state (position) the housekeeper waves (in phase 3 of the interdigestive migrating myoelectric complex, IMMC, which occurs every 1-2 hours (8)), and the device properties, such as size, density, inflation mechanism and other formulation factors.
3. Bioadhesive System.
Intensive studies have been carried out since this approach was first published by Park and Robinson in 1984 (16), on a wide range of natural and synthetic polymers for their bioadhesive properties. Anionic polymers such as sodium carboxy methyl cellulose has a better bioadhesive properties than the neutral and cationic polymers. This finding was disputed later when other cationic polymers were successfully tested (17). Bioadhesive polymers can provide a good vehicle for delivery of drugs to a number of mucosal surfaces in addition to the gastric mucosa. The system can be designed by incorporation of the drug and other excepients within the bioadhesive polymers. On swallowing, the polymer hydrates and adheres to the mucus membrane of the stomach. The mechanism of the adhesion is thought to be through the formation of electrostatic and hydrogen bonding at the polymer-mucus boundary.
A group of researchers (18) have applied the commercially available sucralfate (an aluminum salt of disaccharide used in healing duodenal and gastric ulcer) as a bioadhesive polymer. For a gastric retention system in combination with high viscosity methocel, the compressed tablet was found to adhere to a glass surface and remained intact for at least 24 hours in a 0.1N hydrochloric acid. In this media the sucralfate react with hydrochloric acid to form a very tacky gel. It is believed that sucralfate exerts its healing action not by neutralising the excess acid but by mechanically adhering to the proteinaceous exudate at the ulcer site.
Ideally the muco-adhesive polymer should adhere to the gastric mucus layer until it is removed spontaneously from the surface by various physiological factors. The differences in the physico-chemical nature of these polymers and the variation of inter and intra individual physiological factors such as peristalsis and mucin turnover rate, gastric pH and fast/fed state and type of foods make prediction of removal difficult.
Although there is a substantial amount of literature relating to the gastroadhesive properties of a wide range of polymeric materials, the appropriate successful candidate has yet to be found. Proper selection and evaluation of a successful gastroadhesive polymer involves developing several in vitro and in vivo reproducible methods to quantify the interaction between the polymer and mucosal surface under different extreme conditions. All factors directly and indirectly effecting the adhesion properties should be carefully and intensively studied.
Carbopol and polycabophil were reported to have excellent mucoadhesive properties when tested in animals. Despite these animal successes, test in humans have shown rather disappointing results. Although, there is about a 3 hour delay in gastric emptying in fasted state of animals, there is only 1-1.5 hour delay in fasting humans (19, 20). In spite of the excellent bioadhesive properties of polycarbophole and carbopol through numerous hydrogen bonds provided by the carboxyl group, the disappointing results are believed to be due to the fast turnover of gastric mucin in man.
4. Ion Exchange Resin.
In a published study (21), fast dissolving freeze dried tablets containing an anionic ion-exchange resin (Duolite AP-143) revealed prolonged gastric residence and uniform distribution of the resin within the stomach regardless their particle size distribution. The ion-exchange resin, unlike the water soluble non-absorbable marker diethylenetriaminepenta-acetic acid co-administered with the resin was retained in the stomach for up to 5 hours. It has been suggested that the ion-exchange resin contained in the dosage form may have inherent bioadhesive properties similar to highly charged polymers. As only one in vivo study was carried out, further in vitro and in vivo studies under different physical and physiological condition are required to justify whether the anionic exchange-resin is a suitable candidate as gastroadhesive agent.
In another human study (10,11), radio labeled ion-exchange resin loaded with bicarbonate ions and coated with ethyl cellulose resided in the stomach significantly longer than non loaded ion-exchange resin treated in the same way. In the stomach, chloride ions readily exchange the bicarbonate ions to generate carbon dioxide. The released carbon dioxide inflates the coated membrane, helping the resin to float. The resin keeps floating while there are bicarbonate ions available and ready to exchange with the chlorine ions in the stomach. Prolonging the gastric residence by a floating system increases the chance of drug release in the fundus and cardiac regions of the stomach for local use.
5. Magnetically Controlled Gastric Residence.
A bilayer tablet comprising of a drug layer made of drug, hydroxypropylmethylcellulose, HPMC, and lactose and a magnetic layer made of ultra fine ferrite and HPMC has been developed. Each layer was separately compressed into tablets. The compressed magnetic layer was then coated with water insoluble ethyl-vinyl acetate copolymer. After drying, the coated magnetic layer was stuck to the drug layer with cyanoacrylate-type adhesive.
An in vivo animal study was performed comparing orally administered single layer tablets (drug only layer without the magnetic layer) with bilayer tablets (both the drug and the magnetic layers). To increase the gastric residency time, a magnetic field of 1000-2600 G was applied. The gastric residency and the drug bioavailability of the bilayer tablets were significantly increased by the application of the magnetic field.
In a series of studies, this concept was shown to work but is rather difficult to undertake practically and realise a commercially viable dosage form. Locating the exact position of the magnetic field to the magnetic dosage form in the stomach for each individual may be not easy. In addition, the safety of applying of more than 1000-G magnetic field is unproven.